Quinuclidine derivative

ABSTRACT

Provided is a novel therapeutic agent for chronic obstructive pulmonary disease. 
     Provided are a quinuclidine derivative and a medicament comprising the quinuclidine derivative. 
     
       
         
         
             
             
         
       
     
     wherein R 1  represents a hydrogen atom, a halogen atom, a lower alkyl group, a haloalkyl group, a lower alkoxy group, or a haloalkoxy group; Y represents —C(C═O)—O—, —CH 2 —, or —CH 2 O—; m represents an integer of 1 to 5; Z represents an oxygen atom or a sulfur atom; l represents a number of 0 or 1; n represents an integer of 0 to 4; X −  represents an anion; and a substituent of a quinuclidine ring represents a 1,3-bond, or 1,4-bond, provided that when m is 3, l is 1, and n is 0, R 1  represents a halogen atom, a lower alkyl group, a haloalkyl group, a lower alkoxy group, or a haloalkoxy group.

TECHNICAL FIELD

The present invention relates to a quinuclidine derivative, and to amedicament containing the quinuclidine derivative.

BACKGROUND ART

Chronic obstructive pulmonary disease (COPD) is a generic term fordiseases that have been conventionally called chronic bronchitis oremphysema. COPD is a chronic disease of the lungs, which is caused bylong-term inhalation exposure of harmful substances mainly containingtobacco smoke, and is said to be a lifestyle-related disease that occursin middle-aged or older people against the background of smoking habit.

In the drug therapy for COPD, a bronchodilator (an anticholinergic drug,a β₂-agonist, or a theophylline drug) is mainly used, and an inhaledanticholinergic drug or an inhaled β₂-agonist that mainly dilates thebronchi for a long time is used. In addition, an inhaled corticosteroidis used in severe cases.

In recent years, as a drug effective for the treatment of COPD, forexample, a quinuclidine derivative as a muscarinic M₃ receptorantagonist (Patent Literature 1), N-phenylbenzamide having abronchodilation effect (Patent Literature 2), and a substance thatinhibits the production or accumulation of chondroitin sulfateproteoglycans as an emphysema inhibitor (Patent Literature 3), have beenreported.

CITATION LIST Patent Literature

-   Patent Literature 1: WO 2001/004118-   Patent Literature 2: JP 2006-56890 A-   Patent Literature 3: JP 2008-189667 A

SUMMARY OF INVENTION Technical Problem

However, although the quinuclidine derivative and the N-phenylbenzamidehave some degree of the long-term bronchodilation effect, it cannot besaid at present that they have a sufficient therapeutic effect on COPD.

Accordingly, an object of the present invention is to provide a novelcompound having an excellent therapeutic effect on COPD.

Solution to Problem

Therefore, the present inventors have studied to develop a noveltherapeutic drug for COPD, and have extensively studied based on thefindings that a drug having only the long-term bronchodilation effect isnot sufficient as the therapeutic drug for COPD, and a drug having asuppressive effect on chronic inflammation of the lungs together withthe long-term bronchodilation effect is useful for COPD. As a result,the present inventors have found that a compound represented by thefollowing general formula (1) has a long-term bronchodilation effectlasting longer than that of the compound described in Patent Literature1, and further suppresses inflammation of the lungs, therefore, isparticularly useful as a therapeutic drug for COPD; and thus havecompleted the present invention.

That is, the present invention provides the following [1] to [12].

[1] A quinuclidine derivative of the general formula (1),

wherein R¹ represents a hydrogen atom, a halogen atom, a lower alkylgroup, a haloalkyl group, a lower alkoxy group, or a haloalkoxy group; Yrepresents —C(═O)—O—, —CH₂—, or —CH₂O—; m represents an integer of 1 to5; Z represents an oxygen atom or a sulfur atom; l represents a numberof 0 or 1; n represents an integer of 0 to 4; X⁻ represents an anion;and a substituent of the quinuclidine ring represents a 1,3-bond, or1,4-bond, provided that when m is 3, l is 1, and n is 0, R¹ represents ahalogen atom, a lower alkyl group, a haloalkyl group, a lower alkoxygroup, or a haloalkoxy group.

[2] The quinuclidine derivative according to [1], wherein m is aninteger of 2 to 5, l is a number of 0 or 1, and n is a number of 0 or 1.

[3] The quinuclidine derivative according to [1] or [2], wherein m is aninteger of 2 to 5, l is 0 or 1, and n is 0.

[4] The quinuclidine derivative according to any one of [1] to [3],wherein m is 3, and 1 and n are 0.

[5] The quinuclidine derivative according to any one of [1] to [4],wherein the quinuclidine derivative is an (R) isomer.

[6] A medicament, comprising the quinuclidine derivative according toany one of [1] to [51] as an active ingredient.

[7] The medicament according to [6], wherein the medicament is atherapeutic agent for chronic obstructive pulmonary disease.

[8] A pharmaceutical composition, comprising the quinuclidine derivativeaccording to any one of [1] to [5], and a pharmaceutically acceptablecarrier.

[9] Use of the quinuclidine derivative according to any one of [1] to[5] for producing a medicament.

[10] The use according to [9], wherein the medicament is a therapeuticagent for chronic obstructive pulmonary disease.

[11] The quinuclidine derivative according to any one of [1] to [5],wherein the quinuclidine derivative is used for treating chronicobstructive pulmonary disease.

[12] A method for treating chronic obstructive pulmonary disease,comprising administering an effective amount of the quinuclidinederivative according to any one of [1] to [5].

Advantageous Effects of Invention

The quinuclidine derivative (1) of the present invention has a long-termbronchodilation effect lasting longer than before, further suppressesinflammation of the lungs, therefore, is useful as a therapeutic drugfor COPD, and is particularly useful for the treatment of COPD with theinflammation such as chronic bronchitis.

BRIEF DESCRIPTION OF DRAWINGS

FIG. 1 shows effects of the compounds of the present invention onmethacholine-induced airway constriction (1 hour after administration).

FIG. 2 shows effects of the compounds of the present invention andaclidinium (compound of Example 44 in Patent Literature 1) onmethacholine-induced airway constriction (96 hours afteradministration).

FIG. 3 shows effects of the compounds of the present invention onmethacholine-induced airway constriction (120 hours afteradministration).

FIG. 4 shows anti-inflammatory effects of the compounds of the presentinvention and aclidinium.

DESCRIPTION OF EMBODIMENTS

The quinuclidine derivative of the present invention is of the followinggeneral formula (1).

(In the formula, R¹ represents a hydrogen atom, a halogen atom, a loweralkyl group, a haloalkyl group, a lower alkoxy group, or a haloalkoxygroup; Y represents —C(═O)—O—, —CH₂—, or —CH₂O—; m represents an integerof 1 to 5; Z represents an oxygen atom or a sulfur atom; l represents anumber of 0 or 1; n represents an integer of 0 to 4; X⁻ represents ananion; and a substituent of a quinuclidine ring represents a 1,3-bond,or 1,4-bond. Provided that when m is 3, l is 1, and n is 0, R¹represents a halogen atom, a lower alkyl group, a haloalkyl group, alower alkoxy group, or a haloalkoxy group.)

In general formula (1), Y represents —C(═O)—O—, —CH₂—, or —CH₂O—, andmore preferably —C(═O)—O—.

Z represents an oxygen atom or a sulfur atom, and more preferably anoxygen atom.

Examples of the halogen atom represented by R¹ include a fluorine atom,a chlorine atom, a bromine atom, and an iodine atom. Examples of thelower alkyl group include a linear or branched chain alkyl group having1 to 6 carbon atoms, and specific examples of the lower alkyl groupinclude a methyl group, an ethyl group, an n-propyl group, an isopropylgroup, an n-butyl group, an isobutyl group, a sec-butyl group, atert-butyl group, an n-pentyl group, and an n-hexyl group. Among them, amethyl group and an ethyl group are more preferred, and a methyl groupis particularly preferred. Examples of the haloalkyl group include alinear or branched chain alkyl group having 1 to 6 carbon atomssubstituted with 1 to 3 halogen atoms, and specifically include achloromethyl group, a trifluoromethyl group, and a trichloromethylgroup.

Examples of the lower alkoxy group represented by R¹ include a linear orbranched chain alkoxy group having 1 to 6 carbon atoms, and specificallyinclude a methoxy group, an ethoxy group, an n-propyloxy group, anisopropyloxy group, an n-butyloxy group, an isobutyloxy group, asec-butyloxy group, a tert-butyloxy group, an n-pentyloxy group, and ann-hexyloxy group. Among them, a methoxy group and an ethoxy group aremore preferred, and a methoxy group is particularly preferred. Examplesof the haloalkoxy group include a linear or branched chain alkoxy grouphaving 1 to 6 carbon atoms substituted with 1 to 3 halogen atoms, andspecifically include a trifluoromethoxy group, and a trichloromethoxygroup.

R¹ is preferably a hydrogen atom, a halogen atom, a C₁-C₆ alkyl group, ahalo-C₁-C₆ alkyl group, a C₁-C₆ alkoxy group, or a halo-C₁-C₆ alkoxygroup.

The substitution position of R¹ is not particularly limited, andexamples of the substitution position include an ortho position, a metaposition, and a para position. Among them, an ortho position, or a paraposition is preferred, and particularly a para position is morepreferred.

m represents an integer of 1 to 5, preferably an integer of 2 to 5, morepreferably an integer of 2 to 4, and particularly preferably 3. lrepresents a number of 0 or 1. n represents an integer of 0 to 4, morepreferably an integer of 0 to 2, and furthermore preferably 0 or 1.

It is preferred that m is an integer of 2 to 5, l is 0 or 1, and n is 0or 1; more preferred that m is an integer of 2 to 5, l is 0 or 1, and nis 0; and furthermore preferred that m is 3, and 1 and n are 0.

X⁻ represents an anion, and examples of the X⁻ include a halogen anion,a trifluoroacetic acid anion, a sulfuric acid anion, a nitric acidanion, an acetic acid anion, an oxalic acid anion, and a succinic acidanion, and among them a halogen anion, and a trifluoroacetic acid anionare more preferred.

The bonding position of the substituent of a quinuclidine ring is1,3-bond or 1,4-bond, and 1,3-bond is more preferred.

Preferred embodiments of the quinuclidine derivative (1) of the presentinvention are:

(1) Y is —C(═O)—O—, Z is an oxygen atom, R¹ is a hydrogen atom, ahalogen atom, a C₁-C₆ alkyl group, a halo-C₁-C₆ alkyl group, a C₁-C₆alkoxy group, or a halo-C₁-C₆ alkoxy group, m is an integer of 2 to 5, lis 0 or 1, n is 0 or 1, and X⁻ is a halogen ion (provided that when R¹is a hydrogen atom, not satisfy m=3, l=1, and n=0);(2) Y is —C(═O)—O—, Z is an oxygen atom, R¹ is a hydrogen atom, ahalogen atom, a C₁-C₆ alkyl group, a halo-C₁-C₆ alkyl group, a C₁-C₆alkoxy group, or a halo-C₁-C₆ alkoxy group, m is an integer of 2 to 5, lis 0 or 1, n is 0, X⁻ is a halogen ion (provided that when R¹ is ahydrogen atom, not satisfy m=3, =1, and n=0);(3) Y is —C(═O)—O—, Z is an oxygen atom, R¹ is a hydrogen atom, ahalogen atom, a C₁-C₆ alkyl group, a halo-C₁-C₆ alkyl group, a C₁-C₆alkoxy group, or a halo-C₁-C₆ alkoxy group, m is an integer of 2 to 5, 1and n are 0, and X⁻ is a halogen ion; or(4) Y is —C(═O)—O—, Z is an oxygen atom, R¹ is a hydrogen atom, m is aninteger of 2 to 5, 1 and n are 0, and X is a halogen ion.

In the quinuclidine derivative (1) of the present invention, since thecarbon atom at posit ion 3 of the quinuclidine skeleton is an asymmetriccarbon atom, optical isomers exist. As the optical isomers, both anoptically active isomer and a racemic isomer are included, and an (R)isomer is particularly preferred.

The quinuclidine derivative (1) of the present invention can beproduced, for example, in accordance with the following reaction scheme.

(In the formulae, Hal represents a halogen atom, Y, Z, R¹, l, m, and nare as defined above)

That is, the quinuclidine derivative (1) can be produced by reacting acompound (2) with a compound (3).

The reaction of the compound (2) with the compound (3) easily proceedsby heating to a temperature approximately room temperature to 100° C. Asthe reaction solvent, for example, dioxane, or acetonitrile can be used.Further, as the halogen atom (Hal) of the compound (2), for example, abromine atom, or a chlorine atom is used.

The starting material compound (2) (the following compounds (2-a),(2-b), and (2-c)) can be produced, for example, in accordance with thefollowing reaction schemes.

(In the formulae, R² represents an alkyl group)

That is, a compound (2-a) can be obtained by condensing benzylic acid(4) and quinuclidinol (5). The reaction of the benzylic acid (4) and thequinuclidinol (5) is preferably performed in the presence of acondensing agent such as carbonyldiimidazole (CDI). The reaction ispreferably performed in the presence of a polar organic solvent such asdimethylformamide, or diethylformamide. The reaction is preferablyperformed at a temperature of from room temperature to the boiling pointof the solvent for 1 to 24 hours while stirring the mixture.

By reacting a compound (6) with a compound (7), a compound (2-b) can beobtained. The reaction of the compound (6) with the compound (7) is aGrignard reaction, and for example, is preferably performed at atemperature of from room temperature to the boiling point of the solventfor 30 minutes to 24 hours in a solvent such as tetrahydrofuran whilestirring the mixture.

By reacting a compound (8) with quinuclidinol (5), a compound (2-c) canbe obtained. The reaction of the compound (8) and quinuclidinol (5) is,for example, preferably performed at a temperature of from roomtemperature to the boiling point of the solvent for 1 to 24 hours in apolar organic solvent such as dimethylformamide, or diethylformamide inthe presence of a base such as sodium hydride while stirring themixture.

The compound (2) may be used in the next reaction after being isolatedor without being isolated. After completion of the reaction, theresultant product can be purified by extraction, solvent removal bydistillation, or chromatography. Further, the purification of the object(1) of the present invention can also be performed in the similarmanner.

In addition, in order to obtain the optically active isomer of thecompound (1) of the present invention, (+) quinuclidinol, (−)quinuclidinol, (+) quinuclidine acetic acid ester, or (−) quinuclidineacetic acid ester may be used.

The quinuclidine derivative (1) of the present invention has apersistent and powerful bronchodilation effect, and further has anexcellent anti-inflammatory effect, as shown in the Examples describedlater, therefore, is useful as a therapeutic agent for COPD withsymptoms of emphysema and chronic bronchitis. In particular, thequinuclidine derivative (1) is useful as a therapeutic drug for COPDaccompanied by inflammation.

Examples of the dosage form of the therapeutic agent for COPD of thecompound (1) of the present invention include an inhalant, a transairwayagent, nose drops, an injection, an oral agent (a tablet, granules,powders, and a capsule), ointment, cream, patch, and a suppository.Among them, an inhalant, a transairway agent, nose drops, and an oralagent are particularly preferred. In order to form the compound (1) intothese forms of a pharmaceutical composition, the compound (1) can beformulated together with a pharmaceutically acceptable carrier. Examplesof the carrier include water, ethanol, propylene glycol, polyethyleneglycol, lactose, glucose, D-mannitol, starch, crystalline cellulose,calcium carbonate, kaolin, starch, gelatin, hydroxypropyl cellulose,hydroxypropyl methyl cellulose, polyvinyl pyrrolidone, ethanol,carboxymethyl cellulose, a carboxymethyl cellulose calcium salt,magnesium stearate, talc, acetyl cellulose, white soft sugar, titaniumoxide, benzoic acid, paraoxybenzoic acid ester, sodium dehydroacetate,gum arabic, tragacanth, methylcellulose, egg yolk, surfactant, whitesoft sugar, simple syrup, citric acid, distilled water, ethanol,glycerin, propylene glycol, macrogol, sodium monohydrogen phosphate,sodium dihydrogen phosphate, sodium phosphate, glucose, sodium chloride,phenol, thimerosal, paraoxybenzoic acid ester, and sodium hydrogensulfite.

The inhalant and the transairway agent mean a pharmaceutical compositionfor reaching the tissues of, for example, trachea, bronchi, and lungs,are suitably nose drops or a composition suitable for transnasal ortranspulmonary administration, and are effective when administered with,for example, a nebulizer, an atomizer, a dropper, a pipette, or acannula.

The compound (1) of the present invention can be effectively used bybeing administered in combination with, for example, a drug having ananticholinergic effect such as ipratropium, scopolamine, pirenzepine,tiotropium, oxitropium, aclidinium, glycopyrronium, or umeclidinium; ora β2-agonist such as indacaterol, vilanterol, salmeterol, or formoterol.Further, the compound (1) effectively exerts a therapeutic effect byusing a steroid drug in combination.

In addition, the content of the active ingredient (quinuclidinederivative (1)) of the present invention in the pharmaceuticalcomposition preparation of the present invention varies largelydepending on the form of the preparation, and is not particularlylimited, however, is usually 0.01 to 100% by mass, and preferably 1 to100% by mass, based on the total amount of the composition.

The dose of the therapeutic agent for COPD of the present inventionvaries depending on the condition and age of the patient to beadministered, and the administration method, and is preferably 1.0 μg to10 mg per day for an adult as the quinuclidine derivative (1). Inaddition, this dose may also be administered in 1 to 4 divided doses perday, and is preferably once a day.

EXAMPLES

Hereinafter, the present invention will be described in more detail byway of Examples.

Test Example 1 (Human M₃ Receptor Antagonist Activity)

Measurement of the receptor binding ability was performed by using atransgenic human M₃ receptor expression CHO cell membrane,1-[N-methyl-³H] scopolamine methyl bromide ([³H]NMS, specific activityof 82 Cimmol). Protein concentration of the cell membrane was 2 μg perwell, concentration of the [³H]NMS was 1.0 nM.

Range of the antagonist concentration (10⁻⁴ to 10⁻¹¹ M) was tested bycreating a comparison curve. Unspecific binding was measured in thepresence of 1 μM of atropine.

The reagent was adjusted to a total volume of 100 μL with a bindingbuffer (phosphate buffer/saline). The mixture was incubated at roomtemperature for 2 hours so as to reach equilibrium, and then theresultant mixture was transplanted to a GF/C filter plate that had beenpretreated with a washing buffer containing 0.05% polyethyleneimine for1 hour.

The bound [³H]NMS and the free[³H]NMS were separated by rapid vacuumfiltration, and washed three times with a rinse buffer (50 mM of Tris,100 mM of saline, and pH of 7.4). The obtained filter was dried, andthen onto the dried filter, a solid scintillator, MeltiLex A(manufactured by PerkinElmer, Inc.) was fused, and the measurement andquantification were performed by using a β-counter (MicroBeta microplatescintillation counter (Trilux)).

The Ki value was calculated by the following equation. ([L]:[³H]NMSconcentration, Kd: dissociation constant of [³H]NMS)

Ki=IC50/(1+[L]/Kd)

The Ki value (nM) of the obtained compound was shown in each Example.

Example 1

Into 15 mL of dimethylformamide (DMF), 1.5 g (6.57 mmol) of benzylicacid, 997 mg (7.85 mmol) of (±) quinuclidinol, and 1.59 g (9.85 mmol) ofcarbodiimidazole (CDI) were added, and a tertiary amine was obtained.Into 60 ml of dioxane, the obtained tertiary amine (1.6 g, 4.8 mmol),and benzyl bromide (1.08 g, 6.4 mmol) were added to give a compound(1-1) (2.24 g, yield 65%).

¹H NMR (DMSO-d₆): δ=7.26-7.33 (m, 10H), 7.47-7.55 (m, 5H), 6.76 (s, 1H),5.21 (br, 1H), 4.47 (dd, J=13.1, 10.5 Hz, 2H), 3.40 (d, J=7.8 Hz, 1H),3.86 (dd, J=11.2, 8.4 Hz, 1H), 3.32 (m, 2H), 3.25 (d, J=13.9 Hz, 1H),3.01 (br, 1H), 2.22 (br, 1H), 1.51-1.93 (m, 4H)

mp 219.2-220.4° C.

Ki (M₃ receptor)=4.12 nM

Examples 2 to 41

Compounds of Examples 2 to 41 were obtained in the same manner as inExample 1. The Ki values for M₃ receptors of the obtained compounds werealso shown.

Example 2 (Compound (1-2))

¹H NMR (DMSO-d₆): δ=7.24-7.41 (m, 15H), 6.79 (s, 1H), 5.26 (br, 1H),3.91 (m, 1H), 3.35-3.60 (m, 6H), 2.89-3.14 (m, 3H), 2.28 (br, 1H),1.53-1.99 (m, 4H)

mp 223.2-223.9° C.

Ki (M₃ receptor)=0.083 nM

Example 3 (Compound (1-3))

¹H NMR (DMSO-d₆): δ=6.94-7.52 (m, 15H), 6.75 (s, 1H), 5.20 (br, 1H),4.37 (m, 2H), 4.01 (m, 1H), 3.15-3.66 (m, 6H), 3.12 (m, 1H), 2.24 (m,1H), 1.50-1.94 (m, 4H)

mp 213.5-214.2° C.

Ki (M₃ receptor)=0.13 nM

Example 4 (Compound (1-4))

¹H NMR (DMSO-d₆): δ=7.01-7.38 (m, 14H), 6.77 (s, 1H), 5.23 (m, 1H), 4.05(m, 1H), 3.74 (m, 2H), 3.20-3.41 (m, 6H), 3.14 (m, 1H), 2.27 (m, 1H),1.91 (m, 2H), 1.52-1.70 (m, 2H)

mp 223.4-224.1° C.

Ki (M3 receptor)=0.114 nM

Example 5 (Compound (1-5))

¹H NMR (DMSO-d₆): δ=7.02-7.48 (m, 14H), 6.95 (s, 1H), 5.24 (m, 1H), 4.02(m, 1H), 3.89 (m, 2H), 3.21-3.42 (m, 6H), 3.24 (m, 1H), 2.20 (m, 1H),1.45-1.90 (m, 4H)

mp 211.4-212.2° C.

Ki (M3 receptor)=2.39 nM

Example 6 (Compound (1-6))

¹H NMR (DMSO-d₆): δ=6.95-7.62 (m, 14H), 6.89 (s, 1H), 5.22 (m, 1H), 4.04(m, 1H), 3.78 (m, 2H), 3.40-3.60 (m, 6H), 3.21 (m, 1H), 2.22 (m, 1H),1.55-1.98 (m, 4H)

mp 202.9-203.9° C.

Ki (M3 receptor)=0.458 nM

Example 7 (Compound (1-7))

¹H NMR (DMSO-d₆): δ=6.95-7.36 (m, 14H), 6.75 (s, 1H), 5.20 (m, 1H), 4.41(m, 2H), 4.04 (m, 1H), 3.40-3.68 (m, 6H), 3.14 (m, 1H), 2.24 (m, 1H),1.49-1.92 (m, 4H).

mp 182-184° C.

Example 8 (Compound (1-8))

¹H NMR (DMSO-d₆): δ=6.91-7.36 (m, 14H), 6.75 (s, 1H), 5.20 (m, 1H), 4.42(m, 2H), 4.04 (m, 1H), 3.40-3.69 (m, 6H), 3.12 (m, 1H), 2.24 (m, 1H),1.49-1.96 (m, 4H).

mp 188-190° C.

Example 9 (Compound (1-9))

¹H NMR (DMSO-d₆): δ=6.95-7.36 (m, 14H), 6.75 (s, 1H), 5.20 (m, 1H), 4.40(m, 2H), 4.03 (m, 1H), 3.39-3.67 (m, 6H), 3.11 (m, 1H), 2.24 (m, 1H),1.49-1.96 (m, 4H).

mp 150-153° C.

Example 10 (Compound (1-10))

¹H NMR (DMSO-d₆): δ=6.80-7.25 (m, 14H), 6.77 (s, 1H), 5.20 (m, 1H), 4.35(m, 2H), 4.04 (m, 1H), 3.39-3.67 (m, 6H), 3.13 (m, 1H), 2.25 (s, 3H),2.24 (m, 1H), 1.49-1.99 (m, 4H).

mp 169-173° C.

Example 11 (Compound (1-11))

¹H NMR (DMSO-d₆): δ=7.22-7.55 (m, 14H), 6.75 (s, 1H), 5.21 (m, 1H), 4.48(m, 2H), 4.04 (m, 1H), 3.41-3.71 (m, 6H), 3.14 (m, 1H), 2.25 (m, 1H),1.50-1.83 (m, 4H).

mp 155-157° C.

Example 12 (Compound (1-12))

¹H NMR (DMSO-d₆): δ=7.12-7.35 (m, 14H), 6.76 (s, 1H), 5.20 (m, 1H), 4.36(m, 2H), 4.00 (m, 1H), 3.46-3.70 (m, 6H), 3.16 (m, 1H), 2.24 (m, 1H),1.48-1.83 (m, 4H).

mp 211-213° C.

Example 13 (Compound (1-13))

¹H NMR (DMSO-d₆): δ=6.95-7.37 (m, 14H), 6.76 (s, 1H), 5.20 (m, 1H), 4.38(m, 2H), 4.04 (m, 1H), 3.40-3.71 (m, 6H), 3.16 (m, 1H), 2.23 (m, 1H),1.48-1.87 (m, 4H).

mp 205-207° C.

Example 14 (Compound (1-14))

¹H NMR (DMSO-d₆): δ=7.47-7.47 (m, 2H), 7.24-7.36 (m, 10H), 6.91-6.93 (m,2H), 6.75 (s, 1H), 5.20 (m, 1H), 4.38 (m, 2H), 3.98-4.04 (m, 1H),3.67-3.68 (m, 2H), 3.40-3.54 (m, 4H), 3.11-3.17 (m, 1H), 2.24 (m, 1H),1.82-1.96 (m, 2H), 1.64-1.70 (m, 1H), 1.48-1.52 (m, 1H).

mp 195-196° C.

Example 15 (Compound (1-15))

¹H NMR (DMSO-d₆): δ=7.61-7.63 (m, 2H), 7.24-7.35 (m, 10H), 6.78-6.80 (m,2H), 6.75 (s, 1H), 5.20 (m, 1H), 4.37 (m, 2H), 3.98-4.03 (m, 1H),3.66-3.67 (m, 2H), 3.39-3.53 (m, 4H), 3.10-3.16 (m, 1H), 2.24 (m, 1H),1.82-1.96 (m, 2H), 1.64-1.70 (m, 1H), 1.48-1.52 (m, 1).

mp 185-188° C.

Example 16 (Compound (1-16))

¹H NMR (DMSO-d₆): δ=7.24-7.36 (m, 10H), 7.09-7.10 (m, 2H), 6.82-6.84 (m,2H), 6.77 (s, 1H), 5.20 (m, 1H), 4.33 (m, 2H), 3.99-4.03 (m, 1H),3.61-3.70 (m, 2H), 3.42-3.54 (m, 4H), 3.11-3.16 (m, 1H), 2.21-2.24 (m,4H), 1.84-1.95 (m, 2H), 1.64-1.70 (m, 1H), 1.47-1.52 (m, 1H).

mp 203-204° C.

Example 17 (Compound (1-17))

¹H NMR (DMSO-d₆): δ=7.22-7.39 (m, 15H), 6.75 (s, 1H), 5.19 (br, 1H),3.89-3.93 (m, 1H), 3.34-3.49 (m, 8H), 3.04-3.09 (m, 1H), 2.23 (br, 1H),1.80-1.94 (m, 2H), 1.60-1.66 (m, 1H), 1.45-1.49 (m, 1H).

mp 176-177° C.

Example 18 (Compound (1-18))

¹H NMR (DMOS-d₆): =7.19-7.39 (m, 15H), 6.75 (s, 1H), 5.20 (br, 1H), 3.93(m, 1H), 3.33-3.40 (m, 2H), 3.14-3.22 (m, 4H), 2.99 (m, 1H), 2.56 (t,J=7.9 Hz, 2H), 2.25 (br, 1H), 1.52-1.97 (m, 6H)

mp 243.1-244.4° C.

Ki (M₃ receptor)=0.014 nM

Example 19 (Compound (1-19) (S) isomer)

NMR is the same as in Example 18

mp 243.2-244.1° C.

Ki (M₃ receptor)=2.09 nM

Example 20 (Compound (1-20))

NMR is the same as in Example 18

mp 210.5-211.1° C.

Ki (M₃ receptor)=0.029 nM

Example 21 (Compound (1-21))

¹H NMR (DMSO-d₆): δ=7.20-7.36 (m, 14H), 6.76 (s, 1H), 5.18 (m, 1H), 3.86(m, 1H), 3.22-3.39 (m, 6H), 3.00 (m, 1H), 2.56 (m, 2H), 1.47-2.22 (m,7H).

mp 131-133° C.

Example 22 (Compound (1-22))

¹H NMR (DMSO-d₆): δ=7.23-7.48 (m, 14H), 6.74 (s, 1H), 5.18 (m, 1H), 3.86(m, 1H), 3.14-3.52 (m, 6H), 2.94 (m, 1H), 2.53 (m, 2H), 1.48-2.23 (m,7H).

mp 194-195° C.

Example 23 (Compound (1-23))

¹H NMR (DMOS-d₆) δ 7.23-7.63 (m, 14H), 6.76 (s, 1H), 5.19 (m, 1H), 3.85(m, 1H), 3.23-3.40 (m, 6H), 2.96 (m, 1H), 2.64 (m, 2H), 1.48-2.23 (m,7H).

mp 168-169° C.

Example 24 (Compound (1-24))

¹H NMR (DMSO-d₆): δ=7.24-7.29 (m, 14H), 6.73 (s, 1H), 5.17 (m, 1H), 3.83(m, 1H), 3.21-3.38 (m, 6H), 3.05 (m, 1H), 2.53 (m, 2H), 1.47-2.22 (m,7H)

mp 211.5-212.1° C.

Ki (M3 receptor)=0.31 nM

Example 25 (Compound (1-25))

¹H NMR (DMSO-d₆): δ=7.18-7.48 (m, 14H), 6.74 (s, 1H), 5.17 (m, 1H), 3.83(m, 1H), 3.11-3.37 (m, 6H), 3.01 (m, 1H), 2.53 (m, 2H), 1.48-2.22 (m,7H)

mp 219.5-219.9° C.

Ki (M3 receptor)=1.26 nM

Example 26 (Compound (1-26))

¹H NMR (DMSO-d₆): δ=7.04-7.65 (m, 14H), 6.75 (s, 1H), 5.18 (m, 1H), 3.85(m, 1H), 3.10-3.38 (m, 6H), 2.98 (m, 1H), 2.51 (m, 2H), 2.21 (m, 1H),1.48-1.90 (m, 6H).

mp 184-185° C.

Example 27 (Compound (1-27))

¹H NMR (DMSO-d₆): δ=7.36-7.66 (m, 14H), 6.75 (s, 1H), 5.18 (m, 1H), 3.85(m, 1H), 3.14-3.39 (m, 6H), 3.14 (m, 1H), 2.63 (m, 2H), 1.49-2.42 (m,7H).

mp 221.5-221.9° C.

Ki (M3 receptor)=0.67 nM

Example 28 (Compound (1-28))

¹H NMR (DMOS-d₆): δ=6.82-7.40 (m, 15H), 5.21 (m, 1H), 3.85 (m, 1H), 3.70(s, 3H), 3.10-3.40 (m, 6H), 2.98 (m, 1H), 2.51 (m, 2H), 1.48-2.22 (m,7H)

mp 218.3-218.9° C.

Ki (M3 receptor)=1.29 nM

Example 29 (Compound (1-29))

¹H NMR (DMOS-d₆): =6.92-7.38 (m, 14H), 6.77 (s, 1H), 5.20 (m, 1H), 3.91(m, 3H), 3.27-3.44 (m, 6H), 3.06 (m, 1H), 1.47-2.11 (m, 7H)

mp 211.1-212.0° C.

Ki (M₃ receptor)=0.19 nM

Example 30 (Compound (1-30))

¹H NMR (DMOS-d₆): δ=6.93-7.38 (m, 14), 6.77 (s, 1H), 5.20 (m, 1H),3.98-4.00 (m, 3H), 3.27-3.45 (m, 6H), 3.04 (m, 1H), 1.47-2.1 (m, 7H)

mp 208.8-210.0° C.

Ki (M₃ receptor)=0.084 nM

Example 31 (Compound (1-31))

¹H NMR (DMOS-d₆): δ=6.75-7.44 (m, 15H), 5.19 (br, 1H), 3.87-3.98 (m,3H), 3.27-3.43 (m, 5H), 3.01 (m, 1H), 1.49-2.46 (m, 8H)

mp 214.5-215.4° C.

Ki (M₃ receptor)=0.32 nM

Example 32 (Compound (1-32))

¹H NMR (DMOS-d₆): δ=7.26-7.58 (m, 14H), 6.75 (m, 3H), 5.19 (br, 1H),3.90 (m, 3H), 3.27-3.41. (m, 6H), 3.04 (m, 1H), 1.47-2.24 (m, 7H)

mp 208.1-209.0° C.

Ki (M₃ receptor)=0.22 nM

Example 33 (Compound (1-33))

¹H NMR (DMOS-d₆): δ=6.75-7.38 (m, 15H), 5.20 (br, 1H), 3.95 (m, 3H),3.27-3.43 (m, 6H), 3.06 (m, 1H), 1.48-2.24 (m, 10H)

mp 218.1-219.3° C.

Ki (M₃ receptor)=0.058 nM

Example 34 (Compound (1-34))

¹H NMR (DMOS-d₆): δ=7.10-7.65 (m, 14H), 6.74 (s, 1H), 5.21 (br, 1H),4.09 (m, 2H), 3.93 (m, 1H), 3.28-3.45 (m, 6H), 3.03 (m, 1H), 1.49-2.25(m, 7H)

mp 210.5-211.2° C.

Ki (M₃ receptor)=2.7 nM

Example 35 (Compound (1-35))

¹H NMR (DMOS-d₆): δ=6.75-7.38 (m, 15H), 5.20 (br, 1H), 3.90 (m, 3H),3.66 (s, 3H), 3.27-3.44 (m, 6H), 3.05 (m, 1H), 1.49-2.24 (m, 10H)

mp 213.4-214.3° C.

Ki (M₃ receptor)=5.89 nM

Example 36 (Compound (1-36))

¹H NMR (DMOS-d₆): δ=7.01-7.38 (m, 14H), 6.76 (s, 1H), 5.20 (br, 1H),4.02 (m, 3H), 3.36-3.45 (m, 6H), 3.06 (m, 1H), 1.48-2.24 (m, 7H)

mp 215.1-216.9° C.

Ki (M₃ receptor)=0.39 nM

Example 37 (Compound (1-37))

¹H NMR (DMOS-d₆): δ=7.27-7.40 (m, 15H), 6.76 (s, 1H), 5.21 (br, 1H),4.46 (s, 2H), 3.85 (m, 1H), 3.46 (t, J=5.8 Hz, 2H), 3.21-3.39 (m, 6H),3.03 (m, 1H), 2.25 (m, 1H), 1.49-1.95 (m, 6H)

mp 228.2-229.9° C.

Ki (M₃ receptor)=2.70 nM

Example 38 (Compound (1-38))

¹H NMR (DMOS-d₆): δ=7.19-7.39 (m, 15H), 6.76 (s, 1H), 5.20 (br, 1H),3.80 (m, 1H), 3.31-3.40 (m, 3H), 3.18 (m, 3H), 2.95 (m, 1H), 2.60 (m,2H), 2.25 (br, 1H), 1.55-1.91 (m, 8H)

mp 224.2-224.9° C.

Ki (M₃ receptor)=0.63 nM

Example 39 (Compound (1-39))

¹H NMR (DMOS-d₆): δ=6.91-7.40 (m, 15H), 6.77 (s, 1H), 5.20 (br, 1H),3.99 (t, J=5.4 Hz, 2H), 3.86 (m, 1H), 3.19-3.41 (m, 6H), 3.01 (m, 1H),2.26 (br, 1H), 1.49-1.98 (m, 8H)

mp 194.5-195.5° C.

Ki (M₃ receptor)=2.98 nM

Example 40 (Compound (1-40))

¹H NMR (DMOS-d₆): δ=7.15-7.40 (m, 15H), 6.77 (s, 1H), 5.23 (br, 1H),3.82 (m, 1H), 3.26-3.34 (m, 3H), 3.10-3.22 (m, 3H), 2.96 (m, 1H), 2.58(t, J=7.6 Hz, 2H), 2.25 (m, 1H), 1.21-1.98 (m, 10H)

mp 201.1-202.4° C.

Ki (M₃ receptor)=2.53 nM

Example 41 (Compound (1-41))

¹H NMR (DMOS-d₆): δ 7.27-7.48 (m, 15H), 6.77 (s, 1H), 5.20 (br, 1H),4.49 (br, 1H), 3.96 (m, 1H), 3.80 (m, 3H), 3.37-3.63 (m, 7H), 3.22 (m,1H), 2.26 (m, 1H), 53-1.95 (m, 3H)

mp 222.3?223.3° C.

Ki (M3 receptor)=0.12 nM

Example 42 (Compound (1-42))

(1) Under an Ar atmosphere, 2.00 g of benzyl acid and 16 mL of dry DMFwere charged, and then 2.13 g of CDI was dividedly added to the mixtureat 25° C. to 30° C. over 10 minutes. After that, the resultant mixturewas stirred at the same temperature for 1 hour.

Next, into the resultant mixture, 1.23 g of quinuclidinol was added at5° C. to 10° C., and then 0.351 g of NaH (60%) was added to the mixture.The resultant mixture was stirred at 20° C. to 30° C. for 4 days.

The reaction mixture was cooled down to an internal temperature of 5° C.to 10° C., and was slowly added dropwise to 120 mL of water (whitecrystals precipitated). The mixture was aged and stirred at an internaltemperature of 5° C. to 10° C. for around 6 hours, and then theprecipitated crystals were collected by filtration, washed with 20 mL×3of water, dried at 50° C. to 55° C. for 4 hours under reduced pressure,to give quinuclidinol benzilic acid ester as white crystals.

(2) Under an Ar atmosphere, 1.50 g of quinuclidinol benzilic acid esterand 30 mL of dry acetone were charged, and then 1.35 mL of3-phenylpropyl bromide was added to the mixture at 20° C. to 30° C. Theresultant mixture was stirred at the same temperature for 2 days (45 h).

The reaction mixture was ice-cold stirred for 4 hours, and then theprecipitated crystals were collected by filtration, washed with 30 mL(20V)×3 of isopropyl ether (IPE), and dried at a bath temperature of 50°C. to 55° C. for 3 hours under reduced pressure, to give the targetobject (1.86 g) as white crystals.

¹H NMR (DMSO-d₆): δ=7.21-7.36 (m, 15H), 6.62 (s, 1H), 3.57-3.60 (m, 6H),3.16-3.31 (m, 2H), 2.52-2.60 (m, 2H), 2.26-2.30 (m, 6H), 1.93-1.96 (m,1H).

mp 231-234° C.

Example 43 (Compound (1-43))

(1) Under an Ar atmosphere, 7.49 mL of diethylphosphonoacetic acid ethylester and 68 mL of dry tetrahydrofuran (THF) were charged, and then 1.5g of NaH (60%) was added to the mixture at 8° C. to 15° C. The resultantmixture was stirred at the same temperature for 30 minutes.

Next, to the mixture, 17 mL of dry THE solution of 4.27 g ofquinuclidine-3-one was added dropwise. The resultant mixture was stirredat room temperature for 3 hours, and then stirred at 50° C. to 55° C.overnight.

After confirming the disappearance of the starting materials bythin-layer chromatography (TLC), the reaction mixture was poured into200 mL of ice water and 200 mL of ethyl acetate (EtOAc), and theresultant mixture was stirred for a while.

After the standing and the liquid separation, the obtained organic layerwas washed successively with 200 mL of saline solution, and then theorganic layer was dried over anhydrous magnesium sulfate andconcentrated under reduced pressure to obtain concentrated residues.

The obtained concentrated residues were purified by silica gel columnchromatography (120 g of NH silica gel, Heptane/EtOAc=9/1 to 1/1), togive 3-quinuclidylidene-acetic acid ethyl ester (6.43 g) as colorlessoil.

(2) The compound obtained in (1) in an amount of 6.00 g and 60 mL ofEtOH were charged, and then 0.6 g of 10% Pd—C (50% wet) was added to themixture. The resultant mixture was hydrogenated stirred overnight atnormal pressure and room temperature under a H₂ atmosphere.

After confirming the disappearance of the starting materials by TLC, thePd—C was filtered through Celite, and washed with EtOH, the filtrate wasconcentrated under reduced pressure, to give quinuclidine-3-acetic acidethyl ester (6.05 g, yield 99.8%) as colorless oil.

(3) Under an Ar atmosphere, 2.30 g of quinuclidine-3-acetic acid ethylester and 22 mL of dry THF were charged, and then 1.90 mL of 3MPhMgBr/THF solution was added dropwise to the mixture at 4° C. to 6° C.over 30 minutes The resultant mixture was stirred at 50° C. to 55° C.for 4 hours.

After confirming the disappearance of the starting materials by TLC, thereaction mixture was ice-cooled, and into the cooled mixture, 20 mL of asaturated NH₄Cl aqueous solution was slowly added dropwise, and thereaction was quenched.

The precipitated solid was collected by filtration, washed with H₂O, anddried under reduced pressure, to give 37.0 g of a treated crude productof the target object (37.0 g) as white crystals. The obtained productwas purified by silica gel column chromatography (37 g of NH silica gel,CHCl₃/MeOH=10/1), and then the purified product was concentrated underreduced pressure to obtain fractions containing the target object.

The obtained residues were crystallized by MeOH-THF-IPE, to give thetarget object (b) (1.86 g) as white crystals.

(4) Under an Ar atmosphere, 1.86 g of a compound (b) and 37 mL of dryacetone were charged, and then 1.84 mL of 3-phenylpropyl bromide wasadded to the mixture at 20° C. to 30° C. The resultant mixture wasstirred at the same temperature for 4 days (90 h).

The reaction mixture was ice-cold stirred for 2 hours, and then theprecipitated crystals were collected by filtration, washed with 40 mL×3of IPE, and dried at 50° C. to 55° C. for 3 hours under reducedpressure, to give a treated crude product of a compound (1-42) (2.48 g)as white crystals. After dissolving 2.48 g of the crystals by MeCN—H₂O,the resultant mixture was crystallized by MeCN, to give the compound(1-42) (0.905 g) as white crystals.

¹H NMR (DMSO-d₆): δ=7.18-7.47 (m, 15H), 5.68 (s, 1H), 3.22-3.31 (m, 3H),3.02-3.06 (m, 3H), 2.44-2.57 (m, 5H), 1.62-2.12 (m, 7H).

mp 194-197° C.

Example 44 (Compound (1-44))

(1) Under an Ar atmosphere, 14.49 g of trimethylsulfonium iodide and 60mL of dry dimethyl sulfoxide (DMSO) were charged, and then 2.63 g of NaH(60%) was dividedly added to the mixture at 20° C. to 30° C. Theresultant mixture was stirred at the same temperature for 1.5 hours.

Next, to the mixture, 10.0 g of benzophenone was dividedly added, andthe resultant mixture was stirred at 45° C. to 52° C. for 1 hour.

After confirming the disappearance of the starting materials by TLC, thereaction mixture was poured into 200 mL of ice water and 200 mL ofEtOAc, and the resultant mixture was stirred for a while.

After the standing and the liquid separation, the obtained organic layerwas washed successively with 200 mL of a saturated NaHCO₃ aqueoussolution and 200 mL of saline solution, and then the organic layer wasdried over anhydrous magnesium sulfate and concentrated under reducedpressure, to give concentrated residues (11.7 g).

The obtained concentrated residues were purified by silica gel columnchromatography (120 g of silica gel, Heptane/EtOAc=60/1 to 40/1 to20/1), and then the column fractions containing the target object wasconcentrated under reduced pressure, to give 1,1-diphenylethylene oxide(3.94 g, yield 36.6%) as colorless oil.

(2) Under an Ar atmosphere, 3.29 g of 3-quinuclidinol and 27 mL of dryDMF were charged, and then 1.03 g of NaOH (60%) was dividedly added tothe mixture at 20° C. to 30° C. The resultant mixture was stirred at 45°C. to 50° C. for 1 hour.

Next, to the mixture, 12 mL of dry DMF solution of 3.90 g of1,1-diphenylethylene oxide was added dropwise, and the resultant mixturewas stirred at an internal temperature of 40° C. to 45° C. overnight.

After confirming the disappearance of the starting materials by TLC, thereaction mixture was ice-cooled, and into the cooled mixture, 160 mL ofH₂O was slowly added dropwise (white crystals precipitated). The mixturewas aged and stirred at an internal temperature of 5° C. to 10° C. foraround 2 hours, and then the precipitated crystals were collected byfiltration, washed with 20 mL×3 of H₂O, dried at 50° C. to 55° C. for 4hours under reduced pressure, to give a treated crude product of thetarget object (c) (4.22 g) as a pale brownish white solid.

The obtained treated crude product in an amount of 4.22 g wasrecrystallized by THF-IPE to give the target object (a) (2.21 g) aswhite crystals.

(3) Under an Ar atmosphere, 2.18 g of phenylpropyl bromide and 44 mL ofdry acetone were charged, and then 2.05 mL of 3-phenylpropyl bromide wasadded to the mixture at 20° C. to 30° C. The resultant mixture wasstirred at the same temperature for 3 days (65 h) (whitesuspension→white suspension).

The reaction mixture was ice-cold stirred for 2 hours, and then theprecipitated crystals were collected by filtration, washed with 40 mL×2of IPE, and dried at 50° C. to 55° C. for 3 hours under reducedpressure, to give a compound (1-44) (3.38 g) as white crystals.

¹H NMR (DMSO-d₆): δ=7.17-7.44 (m, 15H), 5.70 (s, 1H), 3.94-4.05 (m, 3H),3.51-3.62 (m, 1H), 3.27-3.31 (m, 5H), 2.95-3.30 (m, 4H), 2.49-2.56 (m,2H), 1.49-2.42 (m, 7H).

Test Example 2 (Effect on Methacholine-Induced Airway Constriction)<Method>

The increase of airway resistance by methacholine induction wasmeasured. To 4 to 6-week old ICR mice, methacholine at 1 mg/mL wasadministered 5 times by spraying the methacholine for 20 seconds. Aftercompletion of the methacholine administration, the airway resistance wasmeasured by a snap shot technique. All of the data were analyzed byusing FlexiVent software.

The test compound at 47.9 μg/kg was administered to the mice through thetransairway. The mice were exposed 5 times to nebulized methacholine 1hour, 96 hours, and 120 hours after the administration, and the airwayresistance at each time was measured.

The results are shown in FIGS. 1 to 3.

<Results>

As can be seen from the results shown in FIGS. 1 to 3, the compound(1-18) and the compound (1-20) reduced the airway resistance at 47.9μg/kg even 120 hours after the administration. In contrast, as shown inFIG. 2, aclidinium did not reduce the airway resistance when exceeding96 hours after the administration.

Test Example 3 (Effect on Porcine Pancreatic Elastase-InducedInflammation) <Method>

To 4 to 6-week old ICR mice, a test compound was administered oncethrough the transairway. Porcine pancreatic elastase at 100 μg/mouse wasadministered 1 hour after the administration of the test compound.Bronchoalveolar lavage fluid (BALF) was collected from the lungs 24hours after the administration of porcine pancreatic elastase, and thetotal number of cells was measured. The results are shown in FIG. 4.

<Results>

As can be seen from the results shown in FIG. 4, the total number ofcells in BALF was reduced in a dose-dependent manner of the compound(1-18), the compound (1-19), and the compound (1-20). In contrast,aclidinium did not show any beneficial anti-inflammatory effects.

From the results described above, it was found that the compounds of thepresent invention are effective against the inflammatory symptoms causedby porcine pancreatic elastase.

INDUSTRIAL APPLICABILITY

The compounds of the present invention have a long-term bronchodilationeffect, and further show the efficacy against the inflammatory symptomscaused by pancreatic elastase of a porcine animal that is a COPD model,therefore, are extremely useful as a therapeutic agent for COPD having abronchodilation effect and an anti-inflammatory effect at the same time.

1: A quinuclidine derivative of the general formula (1):

wherein: R¹ represents a hydrogen atom, a halogen atom, a lower alkylgroup, a haloalkyl group, a lower alkoxy group, or a haloalkoxy group; Yrepresents —C(═O)—O—, —CH₂—, or —CH₂O—; m represents an integer of 1 to5; Z represents an oxygen atom or a sulfur atom; l represents a numberof 0 or 1; n represents an integer of 0 to 4; X⁻ represents an anion;and a substituent of a quinuclidine ring represents a 1,3-bond, or1,4-bond, provided that when m is 3, l is 1, and n is 0, R¹ represents ahalogen atom, a lower alkyl group, a haloalkyl group, a lower alkoxygroup, or a haloalkoxy group. 2: The quinuclidine derivative accordingto claim 1, wherein: m is an integer of 2 to 5; l is a number of 0 or 1;and n is a number of 0 or
 1. 3: The quinuclidine derivative according toclaim 1, wherein n is
 0. 4: The quinuclidine derivative according toclaim 1, wherein: m is 3; and l is
 0. 5: The quinuclidine derivativeaccording to claim 1, wherein the quinuclidine derivative is an (R)isomer. 6: A medicament, comprising the quinuclidine derivativeaccording to claim 1 as an active ingredient. 7: The medicamentaccording to claim 6, wherein the medicament is a therapeutic agent forchronic obstructive pulmonary disease. 8: A pharmaceutical composition,comprising the quinuclidine derivative according to claim 1, and apharmaceutically acceptable carrier. 9-11. (canceled) 12: A method fortreating chronic obstructive pulmonary disease, the method comprisingadministering an effective amount of the quinuclidine derivativeaccording to claim 1.